Heart failure (HF) is a clinical syndrome of growing prevalence and is the final common endpoint of a variety of cardiomyopathic processes including myocardial infarction, hypertensive heart disease, and inherited cardiomyopathies. HF is associated with a poor prognosis, with significant mortality attributed to both progressive ventricular dysfunction and lethal ventricular arrhythmias (VA). Hence there is a clear unmet clinical need to develop novel therapies that can ameliorate the development of cardiac dysfunction and fibrosis as well as target lethal arrhythmias. Serum- and glucocorticoid-regulated kinase-1 (SGK1) is a PI3-kinase (PI3K)-dependent kinase that is activated in pathological hypertrophy and HF but not in physiological hypertrophy. Recent work from our laboratory suggests that SGK1 activation contributes to pathological hypertrophy, cardiac fibrosis, and arrhythmia. In contrast, genetic inhibition of SGK1 mitigates heart failure and fibrosis after biomechanical stress and reduces ischemic injury after in vivo cardiac ischemia-reperfusion, but has no effect on baseline cardiac function. On the basis of these data, we propose that pharmacological inhibition of SGK1 would also mitigate adverse remodeling in different models of cardiac pathology, reducing cardiac dysfunction, fibrosis and arrhythmia without having an adverse effect at baseline. Currently there are no specific inhibitors of SGK1 available. We now propose to use an innovative computer aided drug discovery (CADD) platform to identify and optimize small molecule inhibitors of SGK1. In Specific Aim 1, we will use structure- and ligand-based virtual screens of small molecule libraries to identify "hit" compounds that inhibit SGK1 activity. The activity of these compounds will be evaluated using an in vitro fluorescence polarization kinase assay. Importantly, all small molecule "hits" are pre-filtered for optimized ADMET (adsorption, distribution, metabolism, excression and toxicity) metrics, which eliminates compounds/chemotypes that are likely to be triaged in late stage evaluation. In Specific Aim 2, we will further characterize the top candidates for their ability to specifically and effectively inhibit SGK1 in vitro in cardiomyocytes. Using adenoviral gene transfer to create cardiomyocyte validation models in which SGK1 or closely related kinases (Akt1, ILK) are specifically activated or inhibited, the candidate inhibitors will be tested for their specificity and selectivity. Finally, in Specific Aim 3, we will begin to examine the in vivo efficacy and specificity of identified inhibitors using both wildtype mice and unique in vivo mouse models of cardiac SGK1 activation or inhibition. The identification of specific and effective inhibitors for SGK1 would not only provide us with useful tools for our ongoing investigation of SGK1's role in disease pathogenesis but could also provide a small molecule therapeutic lead for strategies treating heart failure and its complications. PUBLIC HEALTH RELEVANCE: Heart failure is a clinical syndrome of growing prevalence and a major cause of morbidity and mortality throughout the world. Hence there is a clear unmet clinical need to develop novel therapies that can ameliorate this important clinical condition. Studies from our group and others using genetically engineered animal models have suggested that inhibition of the kinase, SGK1, could have significant benefits in heart failure and its sequelae. Although there are currently no known pharmacological inhibitors of SGK1, kinases have been considered good targets for drug development in other settings. In this project, we propose to use an innovative computer aided drug discovery approach to identify inhibitors of SGK1. Top candidates will be characterized for their ability to specifically and effectively inhibit SGK1 in isolated heart muscle cells and in hearts of animals. The identification of specific and effective inhibitors for SGK1 would not only yield useful tools for ongoing investigation of disease mechanisms but could also provide a foundation for novel therapeutic approaches to heart failure and its complications.